The present invention relates to an enhancer of insulin secretion and a medicament for the treatment of diabetes, which comprise a condensed purine derivative as an active ingredient.
Diabetes is a metabolic abnormality mainly of glycometabolism, resulting from insufficient insulin secretion, decreased sensitivity of target cells of insulin and so forth, and principally characterized by noticeable hyperglycemia. If the hyperglycemia continues for a long period of time, serious complications arise in various organs and nerves such as retinopathy, nephropathy and neuropathy, which are caused mainly by vascular lesion. Therefore, for the treatment of diabetes, it is extremely important to control and maintain blood glucose level at a normal level, and methods for that purpose have been studied since old days.
For a type of diabetes where onset is gradual and insulin therapy is not necessarily required for life support (non-insulin dependent diabetes: NIDDM), blood glucose level can be controlled by combination of exercise therapy and drug therapy. As the drugs, insulin secretion enhancers, one of orally available hypoglycemic agents, have widely been used clinically. However, since currently available insulin secretion enhancers all promote insulin secretion non-dependently on glucose level, they cause problems of severe hypoglycemia or insufficient control of blood glucose if doses are not appropriate, and are not fully satisfactory drugs. If a hypoglycemic agent can be provided that is capable of enhancing insulin secretion dependently on a blood glucose level, the agent is expected to be extremely useful for blood glucose control of patients suffering from diabetes because the risk of hypoglycemia due to an excess dosage can be avoided.
As purine derivatives, the compounds of the following formula (I) having diuretic action, antiasthmatic action, anti-dementia action, bronchodilatation action, antiallergic action, antiulcer action and so forth are known (Japanese Patent Unexamined Publication (Kokai) No.3-204880/1991; Journal of Medicinal Chemistry, vol. 35, p.3578, 1992; Journal of Medicinal Chemistry, vol. 36, p.2508, 1993; International Publication WO98/15555). Journal of Medicinal Chemistry, vol. 23, p.1188, 1980 discloses that the compounds represented by the formula (A) have bronchodilatation action. Furthermore, Journal of Medicinal Chemistry, vol. 40, p.3248, 1997 discloses that the compounds represented by the formula (B) have inhibitory action against type IV phosphodiesterase (bronchodilatation action). 
An object of the present invention is to provide a medicament useful for the therapeutic treatment of diabetes and the prophylactic and/or therapeutic treatment of complications of diabetes. More specifically, the object of the present invention is to provide a medicament having action of enhancing insulin secretion in a blood glucose level-dependent manner.
The inventors of the present invention conducted various studies to achieve the foregoing object. As a result, we found that the compounds represented by the following general formula (I) have insulin secretion enhancing action, and that the compounds are useful as an active ingredient of a medicament for the treatment of diabetes. The present invention was achieved on the basis of these findings.
The present invention thus provides medicaments for the therapeutic treatment of diabetes which comprise compound represented by the general formula (I) or a physiologically acceptable salt thereof as an active ingredient: 
wherein R1 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R2 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group; R3 represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group; X1 and X2 independently represent a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group; and n represents an integer of from 0 to 3. The invention also provides medicaments for the prophylactic and/or therapeutic treatment of a complication of diabetes which comprise the aforementioned compound or a physiologically acceptable salt thereof as an active ingredient.
According to other aspects of the present invention, there are provided hypoglycemic agents comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient, and insulin secretion enhancers comprising a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient. These medicaments are preferably provided in the form of a pharmaceutical composition which comprises a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof and one or more of pharmaceutical additives.
According to other aspects of the present invention, there are provided use of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof for the manufacture of the aforementioned medicaments; a method for the therapeutic treatment of diabetes which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human; a method for enhancing insulin secretion which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human; and a method for decreasing blood glucose level which comprises the step of administering a therapeutically effective amount of a compound represented by the aforementioned formula (I) or a physiologically acceptable salt thereof to a mammal including human.
The compounds represented by the general formula (I) will be hereinafter referred to as Compound (I).
Meanings of terms used herein are as follows. As the lower alkyl group or a lower alkyl moiety of a functional group containing the lower alkyl moiety (for example, an aralkyl group), an alkyl group having about 1 to 10 carbon atoms can be used, and the term xe2x80x9calkyl groupxe2x80x9d includes linear, branched and cyclic alkyl groups as well as those consisting of a combination thereof. A cyclic alkyl group or a cyclic alkyl moiety of an alkyl group may have one or more rings, and may have, for example, a bicyclic ring or tricyclic ring system.
Examples of the linear or branched lower alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group and so forth. Examples of the cyclic lower alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a noradamantyl group, an adamantyl group and so forth.
Preferred examples of the lower alkyl group represented by R1 include a linear or branched lower alkyl group (for example, a tert-butyl group, etc.), a monocyclic to tricyclic lower cycloalkyl group (for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 3-noradamantyl group, etc.) and a lower alkyl group substituted with a lower cycloalkyl group (for example, a cyclopropylmethyl group, a cyclopentylmethyl group, etc.). Among them, a 3-noradamantyl group and a cyclopentyl group are more preferred. As the lower alkyl group represented by R2, a linear or branched lower alkyl group (for example, a methyl group, an ethyl group, a n-propyl group, etc.), a monocyclic lower cycloalkyl group or a lower alkyl group substituted with a lower cycloalkyl group (for example, a cyclopropylmethyl group etc.) is preferred. Among them, a n-propyl group is more preferred. As the lower alkyl group represented by R3, a linear or branched lower alkyl group (for example, a methyl group, an ethyl group, etc.) is preferred, and a methyl group is more preferred. As the lower alkyl group represented by X1 or X2, a linear or branched lower alkyl group (for example, an ethyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, etc.), a monocyclic lower cycloalkyl group, or a lower alkyl group substituted with a lower cycloalkyl group (for example, a cyclohexylmethyl group etc.) is preferred. Among them, an ethyl group, an isopropyl group, an isobutyl group, and a tert-butyl group are more preferred.
As the aryl group or an aryl moiety of a functional group containing the aryl moiety (for example, an aralkyl group), an aromatic group consisting of a single ring or two or more condensed rings can be used. More specifically, an aryl group having 6 to 14 ring-membered carbon atoms is preferred. For example, a phenyl group, a naphthyl group, an indenyl group, an anthranyl group or the like may preferably be used. As the aralkyl group, for example, an aralkyl group having 7 to 15 carbon atoms can be used. More specifically, a benzyl group, a phenethyl group, a diphenylmethyl group, a naphthylmethyl group or the like may be used.
As the aromatic heterocyclic group, an aromatic heterocyclic group consisting of a single ring or two or more condensed rings can be used. The kind and number of hetero atom(s) contained in the aromatic heterocyclic group are not particularly limited. For example, one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom may be contained. More specifically, an aromatic heterocyclic group containing about 6 to 14 ring-membered carbon atoms is preferred. For example, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a triazinyl group, an indolyl group, an indazolyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a purinyl group or the like may preferably be used.
When the aryl ring (including the aryl ring of an aralkyl group) or the aromatic heterocyclic ring has substituent(s), the kind, number and substitution position of the substituent(s) are not particularly limited. When two or more substituents exist, they may be the same or different. For example, the rings may have about 1 to 3 substituents. Examples of the substituents on the aryl ring or the aromatic heterocyclic ring include a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a hydroxyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted aroyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkylsulfonyl group, a carboxyl group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted lower alkanoyl group, a halogen atom (the xe2x80x9chalogen atomxe2x80x9d used in the present specification may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), a nitro group, an amino group, a mono- or di(lower alkyl)-substituted amino group, a cyano group, a methylenedioxy group, an ethylenedioxy group and the like.
In the aforementioned functional groups, the above-explained groups may be used as the lower alkyl or a lower alkyl moiety of the functional groups containing a lower alkyl moiety (for example, the aralkyl group, the lower alkoxy group, the aralkyloxy group, the lower alkoxycarbonyl group, the lower alkylthio group, the lower alkylsulfonyl group, the lower alkanoyl group, the mono- or di(lower alkyl)-substituted amino group and the like). When the lower alkyl group or the lower alkyl moiety has substituent(s), the kind, number, and substitution position of the substituent(s) are not particularly limited. When two or more substituents exist, they may be the same or different. For example, the lower alkyl group or the lower alkyl moiety may have about 1 to 3 substituents. Examples of such substituents include a hydroxyl group, a halogen atom, a carboxyl group, a sulfo group, a phosphono group, ester groups derived from these acidic groups (a lower alkyl ester, an aralkyl ester, an aryl ester, etc.) and the like. More specific examples of the substituted alkyl group include a hydroxyethyl group, a trifluoromethyl group and the like. The two lower alkyl groups in the di(lower alkyl)-substituted amino group may be the same or different.
In the aforementioned functional groups, the aralkyl group or an aralkyl moiety of the aralkyloxy group has the same meaning as the aforementioned aralkyl group, and the aryl moiety of the aryl group, the aryloxy group, or the aroyl group has the same meaning as the aforementioned aryl group. As the lower alkenyl group, a linear or branched alkenyl group having 2 to 6 carbon atoms can be used. For example, a vinyl group, an allyl group, a 1-propenyl group, a methacryl group, a butenyl group, a crotyl group, a pentenyl group, a hexenyl group or the like may be used. As the lower alkynyl group, a linear or branched alkynyl group having 2 to 6 carbon atoms can be used. For example, an ethynyl group, a propynyl group, a butynyl group, a pentynyl group, a hexynyl group or the like may be used. The number of unsaturated bond in the alkenyl group or the alkynyl group is not particularly limited, and the number may preferably be 1.
When the aforementioned lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, aralkyloxy group, aryloxy group, or aroyl group has substituent(s), the kind, number, and substitution position of the substituent(s) are not particularly limited. When two or more substituents exist, they may be the same or different. For example, the lower alkenyl group, lower alkynyl group, aralkyl group, aryl group, aralkyloxy group, aryloxy group, or aroyl group may have about 1 to 3 substituents. As the substituents, those exemplified as the substituents of the lower alkyl group may be used.
As the aryl group represented by R1, a phenyl group, a 4-bromophenyl group and the like are preferred. As the aromatic heterocyclic group represented by R1, a furyl group, a thienyl group and the like are preferred. As the aryl group represented by R2, a phenyl group is preferred. As the aralkyl group represented by R2, a benzyl group is preferred. As the aralkyl group represented by R3, a benzyl group is preferred. As the aralkyl group represented by X1 or X2, a phenyl group is preferred. Examples of the aralkyl group represented by X1 or X2 include a benzyl group, a halogenated benzyl group (a 4-fluorobenzyl group, a 3-fluorobenzyl group, a 2-fluorobenzyl group, a 2,3-difluorobenzyl group, a 2,5-difluorobenzyl group, a 4-chlorobenzyl group, a 3-chlorobenzyl group, a 2,5-dichlorobenzyl group, a 4-bromobenzyl group, a 3-bromobenzyl group, an 3-iodobenzyl group, etc.), a 4-tert-butylbenzyl group, a 2-phenylbenzyl group, a 3-trifluoromethylbenzyl group, a 3-trifluoromethoxybenzyl group, a 3,5-bis(trifluoromethyl)benzyl group, a 4-hydroxybenzyl group, a 4-methoxybenzyl group, a 4-nitrobenzyl group, a 3-cyanobenzyl group, a 3-carboxybenzyl group, a 3-phenoxybenzyl group, a 3-(2-fluorophenoxy)benzyl group, a 4-benzyloxybenzyl group, a diphenylmethyl group, a phenethyl group, an xcex1, xcex1-dimethylbenzyl group and the like. When X1 is a group other than a hydrogen atom, X2 is preferably a hydrogen atom. A combination of a lower alkyl group as X1 (for example, a methyl group) and an aralkyl group as X2 (for example, a benzyl group) is also preferred.
In the aforementioned general formula (I), the substitution positions of X1 and X2 are not particularly limited, and they may substitute at any positions on the ring. When X1 or X2 is a substituent other than a hydrogen atom, the absolute configuration of the carbon atom to which it binds may be in either a S- or R-configuration. The symbol xe2x80x9cnxe2x80x9d may preferably be 0.
As the active ingredient of the medicament of the present invention, physiologically acceptable salts of Compound (I) may be used. Such physiologically acceptable salts include acid addition salts such as inorganic acid salts and organic acid salts; base addition salts such as metal salts, ammonium salts and organic amine addition salts; amino acid addition salts and the like. Examples of the physiologically acceptable acid addition salts include inorganic acid salts such as hydrochlorides, sulphates and phosphates, and organic acid salts such as acetates, maleates, fumarates, tartrates, and citrates. Examples of the physiologically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, as well as aluminum salts, zinc salts and the like. Examples of the physiologically acceptable organic amine addition salts include addition salts of organic amines such as morpholine, piperidine and the like. Examples of the physiologically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.
As the active ingredient of the medicament of the present invention, the aforementioned compounds in free forms or physiologically acceptable salts thereof, as well as any hydrates and solvates thereof may be used. The kind of solvents forming the solvates is not particularly limited so long as they are physiologically acceptable. For example, ethanol, acetone and the like may be used. The compounds represented by the formula (I) may have one or more asymmetric carbons. As the active ingredient of the medicament of the present invention, any substances falling within the scope of the general formula (I) may be used, including optical isomers or diastereoisomers in pure forms, any mixtures of isomers, racemates and the like. When the compounds represented by the general formula (I) contain one or more double bonds, each configuration thereof may be in either a Z- or E-configuration.
The methods for the preparation of typical compounds falling within the compounds represented by the formula (I) are specifically disclosed in International Publication WO98/15555, and are also explained in Japanese Patent Unexamined Publication No. 3-204880/1991; Journal of Medicinal Chemistry, vol. 35, p.3578, 1992; Journal of Medicinal Chemistry, vol. 36, p.2508, 1993; Journal of Heterocyclic Chemistry, vol. 30, p.241, 1993 and the like. Furthermore, the methods for preparing preferred compounds shown below will be specifically explained in detail in the examples of the present specification. Therefore, those skilled in the art can prepare any compounds falling within the scope of the general formula (I) according to the processes disclosed in the aforementioned references or the manufacturing processes specifically described in the present specification, or by suitably changing regents and starting materials, and further by appropriately modifying or altering these processes, if necessary.
The intermediate compounds and target compounds obtained in these manufacturing processes can be isolated and purified by methods for purification conventionally used in the field of synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various kinds of chromatography and the like. The intermediate compounds can also be used in subsequent reactions without particular purification. When salts of the compounds represented by the general formula (I) are prepared, the compounds in a free form may be dissolved or suspended in a suitable solvent, and a suitable acid or base is added to the mixture to form a salt, and then the resulting salts may be isolated and purified as required. It is also possible to convert a target substance obtained in a form of salt into a free form, and their converted into a desired salt.
Preferred examples of the active ingredient of the medicament of the present invention include:
(1) those wherein R1 represents a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, R2 represents a lower alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, R3 represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, X1 and X2 independently represent a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and the symbol xe2x80x9cnxe2x80x9d represents 0, or physiologically acceptable salts thereof; more preferred examples include:
(2) those wherein R1 represents a lower alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aromatic heterocyclic group, R2 represents a lower alkyl group or a substituted or unsubstituted aryl group, R3 represents a hydrogen atom or a substituted or unsubstituted aralkyl group, X1 represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted aralkyl group, X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0, or physiologically acceptable salts thereof; and further preferred examples include
(3) those wherein R1 represents a n-propyl group, a n-butyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopropylmethyl group, a cyclopentylmethyl group, an isopropyl group, or a tert-butyl group, R2 represents a n-propyl group or an ethyl group, R3 represents a hydrogen atom, X1 represents a lower alkyl group or a substituted or unsubstituted aralkyl group, X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0, or physiologically acceptable salts thereof.
More specifically, the followings can be exemplified as preferred compounds or physiologically acceptable salts thereof suitable as the active ingredient of the medicament of the present invention. Among them, Compound 16, Compounds 18-20, Compound 23, Compound 31, Compound 35, Compound 37, Compound 43, and Compound 55 are particularly preferred. The compounds in free forms or other physiologically acceptable salts of these salts are also preferred. References disclosing each corresponding compound are indicated in the parentheses after the names of compounds. As for Compound 6, a racemate thereof is disclosed in Japanese Patent Unexamined Publication No.3-204880/1991. It should be understood that the active ingredients of the medicaments of the present invention are not limited to the compounds or physiologically acceptable salts thereof listed below. The compounds specifically disclosed in Japanese Patent Unexamined Publication No. 3-204880/1991 or International Publication WO98/15555 or physiologically acceptable salts thereof, as well as those listed below, are preferred as the active ingredient of the medicament of the present invention.
Compound 1: (R)-8-ethyl-7,8-dihydro-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one L-tartrate (Journal of Medicinal Chemistry, vol.36, p.2508, 1993)
Compound 2: (S)-8-ethyl-7,8-dihydro-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one D-tartrate (Journal of Medicinal Chemistry, vol. 36, p.2508, 1993)
Compound 3: (R)-7,8-dihydro-8-isopropyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 4: (S)-7,8-dihydro-8-isopropyl-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 5: 7,8-dihydro-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 6: (R)-2-cyclopentyl-7,8-dihydro-8-methyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 7: (R)-2-cyclopentyl-8-ethyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one L-tartrate (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 8: (S)-2-cyclopentyl-8-ethyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one D-tartrate (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 9: (R)-2-cyclopentyl-7,8-dihydro-8-isopropyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride (Japanese Patent Unexamined Publication 3-204880/1991)
Compound 10: (S)-2-cyclopentyl-7,8-dihydro-8-isopropyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 11: (R)-2-cyclopentyl-7,8-dihydro-8-isobutyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one L-tartrate
Compound 12: (S)-8-tert-butyl-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 13: 8-butyl-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 14: (S)-8-cyclohexylmethyl-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 15: (R)-2-cyclopentyl-7,8-dihydro-8-phenyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 16: (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 17: (S)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride (Japanese Patent Unexamined Publication No. 3-204880/1991)
Compound 18: 2-cyclopentyl-8-(4-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 19: 2-cyclopentyl-8-(3-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 20: 8-(4-chlorobenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 21: 8-(3-chlorobenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 22: 2-cyclopentyl-8-(2,6-dichlorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 23: 8-(4-bromobenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 24: 8-(3-bromobenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 25: 2-cyclopentyl-7,8-dihydro-8-(4-methoxybenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 26: 2-cyclopentyl-7,8-dihydro-8-(4-nitrobenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 27: (R)-8-(4-benzyloxybenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 28: (S)-8-(4-benzyloxybenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 29: (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-1-methyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 30: 2-cyclopentyl-7,8-dihydro-8-diphenylmethyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 31: 2-cyclopentyl-7,8-dihydro-8-phenethyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 32: (R)-4,8-dibenzyl-2-cyclopentyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 33: (R)-8-benzyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 34: (R)-1,8-dibenzyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 35: (R)-8-benzyl-7,8-dihydro-2,4-dipropyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 36: (R)-8-benzyl-2-cyclopropyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 37: (R)-8-benzyl-2-cyclobutyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 38: (R)-8-benzyl-2-cyclohexyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 39: (R)-8-benzyl-7,8-dihydro-2-(3-noradamantyl)-4-propyl-1-H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 40: (R)-8-benzyl-2-cyclopentylmethyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 41: (R)-8-benzyl-7,8-dihydro-2-isopropyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 42: (R)-8-benzyl-2-(3-furyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 43: (R)-8-benzyl-2-tert-butyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 44: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(3-thienyl)-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 45: 8-(4-bromobenzyl)-2-cyclohexyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 46: 8-(4-chlorobenzyl)-7,8-dihydro-2,4-dipropyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 47: 8-(4-chlorobenzyl)-2-cyclohexyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 48: 8-(4-chlorobenzyl)-2-cyclobutyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 49: 8-(4-fluorobenzyl)-7,8-dihydro-2,4-dipropyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 50: 2-cyclohexyl-8-(4-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 51: (R)-2-cyclobutyl-8-(4-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 52: 2-butyl-8-(4-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 53: 8-(4-fluorobenzyl)-2-(2-furyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 54: (R)-8-(4-fluorobenzyl)-2-(3-furyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 55: (R)-2-tert-butyl-8-(4-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 56: 8-(3-fluorobenzyl)-7,8-dihydro-2,4-dipropyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 57: 2-cyclobutyl-8-(3-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 58: 8-(3-fluorobenzyl)-7,8-dihydro-2-isobutyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 59: 2-(4-bromophenyl)-8-(3-fluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 60: 8-(2-fluorobenzyl)-7,8-dihydro-2-isobutyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 61: 2-cyclopentyl-7,8-dihydro-8-(3-methylbenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 62: 2-cyclopentyl-7,8-dihydro-8-(3-iodobenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 63: 2-cyclopentyl-8-(2,3-difluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 64: 2-cyclopentyl-8-(2,5-difluorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 65: 2-cyclopentyl-8-(2,5-dichlorobenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 66: (S)-8-tert-butyl-7,8-dihydro-2-(3-noradamantyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 67: (S)-8-tert-butyl-2-(3-furyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 68: (S)-8-tert-butyl-2-(3,5-dimethylisoxazol-4-yl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 69: (S)-7,8-dihydro-2,8-diisopropyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 70: 8-(3-cyanobenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 71: (R)-8-benzyl-2-cyclopentyl-4-ethyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one hydrochloride
Compound 72: (R)-8-benzyl-2-cyclopentyl-4-cyclopropylmethyl-7,8-dihydro-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 73: (R)-8-benzyl-2-cyclopropylmethyl-7,8-dihydro-4-propyl-1H-imidazo-[2,1-i]purin-5(4H)-one hydrochloride
Compound 74: 8-(3-carboxybenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 75: 2-cyclopentyl-8-(xcex1, xcex1-dimethylbenzyl)-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 76: (R)-2-cyclopentyl-7,8-dihydro-8-(4-hydroxybenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 77: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(3-pyridyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 78: (R)-8-benzyl-7,8-dihydro-2-phenyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 79: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(2,2,3,3-tetramethylcyclopropyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 80: (R)-8-benzyl-7,8-dihydro-2-(3,4-methylenedioxyphenyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 81: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(4-pyridyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 82: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(2-pyrazyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 83: (R)-8-benzyl-7,8-dihydro-4-propyl-2-(2-thienyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 84: (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-methyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 85: (R)-8-benzyl-2-cyclopentyl-7,8-dihydro-4-phenyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 86: 8-(4-tert-butylbenzyl)-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 87: 2-cyclopentyl-7,8-dihydro-8-(2-phenylbenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 88: 2-cyclopentyl-7,8-dihydro-4-propyl-8-(3-trifluoromethylbenzyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 89: 2-cyclopentyl-8-[3-(2-fluorophenoxy)benzyl]-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 90: 2-cyclopentyl-7,8-dihydro-8-(3-phenoxybenzyl)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 91: 2-cyclopentyl-7,8-dihydro-4-propyl-8-(3-trifluoromethoxybenzyl)-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 92: 8-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopentyl-7,8-dihydro-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
Compound 93: 8-benzyl-2-cyclopentyl-7,8-dihydro-8-methyl-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one
The compounds represented by the general formula (I) or physiologically acceptable salts thereof have insulin secretion enhancing action in cultured xcex2-cells and hypoglycemic action in rats, and accordingly, they are useful as an active ingredient of the medicament for the treatment of diabetes. Further, they are useful as an active ingredient of the medicament for the prophylactic and/or therapeutic treatment of various complications of diabetes, for example, retinopathy, nephropathy, neurosis and the like. As the active ingredient of the medicament of the present invention, one or more substances selected from the group consisting of the compounds represented by the general formula (I) and physiologically acceptable salts thereof, and hydrates thereof and solvates thereof can be used. Although the aforementioned substances, per se, may be administered, it is generally desirable to provide the medicament in a form of a pharmaceutical composition comprising the aforementioned substance as the active ingredient and one or more pharmaceutical additives. The medicament of the present invention can be administered to human and other mammals.
The form of the pharmaceutical composition is not particularly limited, and an appropriate form most suitable for a purpose of the prophylactic or therapeutic treatment can be selected from forms of pharmaceutical preparations for oral or parenteral administration. Examples of pharmaceutical preparations suitable for oral administration include tablets, capsules, powders, granules, subtilized granules, syrups, solutions, emulsions, suspensions, chewable formulations and the like. Examples of pharmaceutical preparations suitable for parenteral administration include injections (for subcutaneous injection, intramuscular injection, intravenous injection or the like), drip infusions, inhalants, sprays, suppositories, transdermal or transmucosal preparations in the forms of gel, ointment or the like, transdermal preparations in the forms of patch, tape or the like. However, the preparations are not limited to these examples.
Liquid preparations suitable for oral administration such as solutions, emulsions and syrups can be prepared by using water, saccharides such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor and peppermint or the like. For the preparation of solid preparations such as capsules, tablets, powders and granules, excipients such as lactose, glucose, sucrose and mannitol, disintegrating agents such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, surface active agents such as fatty acid esters, plasticizers such as glycerin or the like may be used.
Pharmaceutical preparations for injection or drip infusion, which are suitable for parenteral administration, contain the aforementioned substance as the active ingredient preferably in a sterilized aqueous medium isotonic with blood of a recipient in a dissolved or suspended state. For example, as for injections, a solution can be prepared by using an aqueous medium consisting of saline, a glucose solution, or a mixture of saline and a glucose solution. Preparations for enteral administration can be prepared, for example, by using a carrier such as cacao butter or hard fat, and are provided as suppositories. Further, for the preparation of sprays, a carrier may be used which can disperse the aforementioned substance as the active ingredient as fine particles, and facilitate adsorption of the active ingredient without stimulating mucosae of oral cavity and respiratory tract of recipients. Specifically, examples of the carrier include lactose and glycerol. Depending on the properties of the substance as the active ingredient and the carrier, pharmaceutical preparations in forms of aerosol, dry powder and the like can be prepared. To these pharmaceutical preparations for parenteral administration, one or more auxiliary ingredients selected from glycols, oils, flavors, preservatives, excipients, disintegrating agents, lubricants, binders, surface active agents, plasticizers and the like may also be added.
Dose and frequency of administration of the medicament of the present invention may preferably be increased or decreased depending on various factors such as type and severity of diseases, dosage form, conditions of patients such as age and body weight, and presence or absence of complications. In general, the medicament may preferably be administered in an amount of 1 to 1000 mg/kg per day for an adult dividedly as three or four times of administrations.
According to another aspect of the present invention, there are provided the compounds of the general formula (I):
(1) wherein R1 represents a 3-noradamantyl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a hydrogen atom, a tert-butyl group, an isopropyl group, or a benzyl group, X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(2) wherein R1 represents a cyclopentyl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a n-butyl group, an isobutyl group, a tert-butyl group, a cyclohexylmethyl group, an aralkyl group whose alkyl moiety is substituted or an unsubstituted aralkyl group (except for a benzyl group), or an aralkyl group (preferably a benzyl group) having one or more substituents (preferably one or two, more preferably one) selected from the group consisting of a halogen atom, a substituted or unsubstituted lower alkyl group, a lower alkoxyl group (preferably a methoxy group), an aralkyloxy group (preferably a benzyloxy group), a carboxyl group, a cyano group, a hydroxyl group, and a nitro group on the ring, X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(3) wherein R1 represents a cyclopentyl group, R2 represents a n-propyl group, R3 represents a lower alkyl group (preferably a methyl group), X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(4) wherein R1 represents a cyclopentyl group, R2 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), a lower alkyl group (except for a n-propyl group; preferably a cyclopropylmethyl group or a linear lower alkyl group) or a substituted or unsubstituted aryl group (preferably a phenyl group), R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(5) wherein R1 represents a hydrogen atom, R2 represents a n-propyl group, R3 represents a hydrogen atom, or a substituted or unsubstituted aralkyl group (preferably a benzyl group), X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(6) wherein R1 represents a lower alkyl group (except for a cyclopentyl group), a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aryl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
(7) wherein R1 represents a linear or branched lower alkyl group (preferably an isopropyl group) or a substituted or unsubstituted aromatic heterocyclic group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a lower alkyl group (except for a methyl group; preferably an isopropyl group, or an isobutyl group, a t-butyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0; and
(8) wherein R1 represents a cyclopentyl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a methyl group, X2 represents a substituted or unsubstituted aralkyl group, and the symbol xe2x80x9cnxe2x80x9d represents 0.
Specific examples of these compounds include, for example, Compounds 3-5, Compounds 11-14, and Compound 18 to Compound 93.
As preferred compounds, there are provided:
the aforementioned compounds wherein R1 represents a cyclopentyl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents an aralkyl group (preferably a benzyl group) having one or more (preferably one) halogen atoms on the ring or an unsubstituted aralkyl group (except for a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
the aforementioned compounds wherein R1 represents a cyclopentyl group, R2 represents a linear or branched lower alkyl group (except for a n-propyl group), R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0; and
the aforementioned compounds wherein R1 represents a lower alkyl group (except for a cyclopentyl group), R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0;
Particularly preferred compounds are:
the aforementioned compounds where R1 represents a cyclopentyl group, R2 represents an ethyl group, R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0; and
the aforementioned compounds wherein R1 represents a tert-butyl group, R2 represents a n-propyl group, R3 represents a hydrogen atom, X1 represents a substituted or unsubstituted aralkyl group (preferably a benzyl group), X2 represents a hydrogen atom, and the symbol xe2x80x9cnxe2x80x9d represents 0.
As salts of the aforementioned compounds, those explained above can be used. It should be understood that, besides the aforementioned compounds in free forms and physiologically acceptable salts thereof, any hydrates and solvates thereof fall within the scope of the present invention. Further, any isomers, mixtures of isomers, racemates and the like also fall within the scope of the present invention. These compounds and salts thereof are useful as, for example, the active ingredient of the medicament of the present invention. However, utilities of the compounds of the present invention and salts thereof are not limited to said particular utility.